This invention relates generally to drug delivery devices, and more specifically to intravascular catheters for delivery of therapeutic agents from within a lumen of a blood vessel or other body organ.
In percutaneous transluminal angioplasty procedures, a catheter having a dilatation device such as a balloon at its distal end, is positioned in a lumen of a blood vessel with the dilatation device disposed within a stenotic region of the vessel. The dilatation device is then expanded in order to dilatate the vessel and restore adequate blood flow through the region of stenosis.
While angioplasty treatment frequently produces favorable results, it is not without problems. Primary among these are abrupt closure and restenosis. Abrupt closure refers to the acute interruption of blood flow at the site of angioplasty which typically occurs within the initial hours following the procedure. If arterial patency is not restored, acute myocardial infarction and death may occur. The primary mechanisms of abrupt closure are arterial dissection and/or thrombosis. The ability to maintain arterial dissections from occluding the vessel lumen via a deployable mechanism would allow perfusion of distal myocardium and reduce the complications associated with abrupt closure. Furthermore, it is postulated that the ability to deliver agent directly into the arterial wall (e.g. antithrombotic agents) would reduce thrombus formation and hence the incidence of abrupt thrombotic closure.
Restenosis refers to the re-narrowing of a vessel after an initially successful angioplasty procedure. Restenosis usually occurs within the first six months following angioplasty and is due to proliferation and migration of the cellular components of the vessel wall. Local delivery of agent would provide the means to achieve agent tissue concentrations far exceeding what is possible via systemic delivery. It is also postulated that the delivery of agent(s) directly into the arterial wall would interrupt the cellular proliferation and recruitment and hence reduce the incidence restenosis. Other interventional therapies used in the treatment of atherosclerosis, such as atherectomy, in which the stenotic region of the vessel is mechanically debulked to restore adequate blood flow through the stenotic region of the vessel, may equally benefit from such local delivery of agent (s).
The potential utility of local intramural drug delivery is not limited to atherosclerotic coronary artery disease. Other sites of atherosclerosis (e.g. renal, iliac, femoral, distal leg and carotid arteries as well as saphenous vein grafts, synthetic grafts and arterio-venous shunts used for hemodialysis) would also be appropriate vessels for local intramural drug delivery. Local intramural therapy using agent(s) may prove efficacious in non-arterial structures, including the prostrate via the prostatic urethra (benign prostatic hypertrophy, prostatitis and adenocarcinoma), fallopian tubes via its lumen (strictures), and brain parenchyma (Parkinson's Disease).
At present, intravenous medications are delivered systemically by vein, or regionally (e.g. intracoronary infusion). Systemic delivery is not well suited to the treatment of disease entities with a single site of interest (e.g., coronary artery disease) in that is necessitates: 1) exposing sites other than the site of interest to medication where is may have an adverse reaction; 2) sufficiently large quantities of agent within the entire volume of distribution to obtain the desired effect; and 3) exposing the agent to degradation and elimination by an organ system(s) remote from the site of interest. Furthermore, the agent tissue concentration within the site of interest is often limited by the detrimental effects of the agent at distant sites. Local intramural agent delivery obviates these problems. Therefore, it is of particular importance to deliver the therapeutic agent directly to the treatment site by intimate contact with or penetration into the tissue over a substantial portion of the luminal surface, rather than simply releasing the agent into the bloodstream in the vicinity of the treatment site.
While various catheters have been developed for local delivery of drugs to a treatment site within a vessel or organ lumen, such devices have suffered from certain drawbacks. In particular, known treatment apparatus do not permit the delivery of a drug directly to a treatment site independently of the deployment of the delivery interface against the lumen wall. For example, known treatment apparatus frequently employ an expandable member such as a balloon which is expanded at or near the treatment site and brought into contact with the lumen wall. A drug is infused through pores disposed either directly in the wall of the balloon, or in a second expandable member surrounding the balloon. In the former design, the drug itself serves as the expansion fluid for the balloon, with the drug being expelled through the porous surface of the expanded balloon. In the latter case, the drug is first delivered into the outer expandable member, and the balloon is then expanded so as to force the drug through the porous surface in the outer member. In both of these types of drug delivery devices, the drug cannot be infused without expanding the balloon, nor can the timing of drug infusion be controlled independently of balloon expansion.
Moreover, because such devices rely on a balloon-type expansion member to provide deployment of the porous infusion surface against the vessel wall, they completely occlude the vessel in the region of treatment when in their deployed configuration. This severely restricts, or even blocks entirely, blood flow through the vessel during treatment, preventing perfusion of tissue downstream from the treatment site. Therefore, the time such devices may be allowed to remain deployed is very limited, commonly for as little as one to two minutes. Catheters have been developed which have perfusion passages through the catheter shaft to allow blood to bypass through the device and perfuse the tissue downstream. However, due to size limitations and other design constraints, it is difficult to design such perfusion passages with sufficient blood flow capacity to allow deployment of the delivery device for relatively long periods of time. Furthermore, conventional perfusion balloon catheters, while able to maintain the blood vessel patent following a dilatation procedure, suffer from certain drawbacks, including the "flagging" of their amorphous structure when deflated, and the relatively limited vessel size range that a single device can be designed for. No such devices also able to do drug delivery are known to exist. In non-perfusing devices which employ the therapeutic agent itself as the expansion fluid for the balloon, the reversal of fluid flow required to deflate the balloon tends to draw blood into the device, preventing further use of the device until the blood has been expelled and the device has been refilled with agent. Typically, this prevents multiple treatments within the same vessel without withdrawing the catheter for purging or replacement.
It has also been recognized that alternative mechanisms to the existing devices utilizing balloon deployment to infuse an agent are unavailable in known treatment apparatus.
Another field of concern to the present invention is that of cellular seeding for repair of injured arterial tissue following angioplasty or atherectomy treatment. In the past decade there have been great advances in the technology enabling the culturing and transfecting of endothelial cells. Nable et al., have reported the ability to seed autologous endothelial cells transfected with the .beta.-galactosidase gene upon injured arterial surface (Science 1989;xx:1343-44, incorporated herein by reference). Other investigators are working along similar lines. Most investigators have used a catheter system which isolates a site in the vessel by occluding the artery with balloons proximally and distally to that site. Cells are then introduced into the isolated portion. The efficacy of cell transfer by this approach is poor.
An intravascular treatment apparatus is therefore desired which can be used to administer therapeutic agents to a treatment site within the lumen of a blood vessel or other organ by direct contact with a substantial portion of the interior wall thereof. Desirably, the treatment apparatus will be deployable against the treatment site independently of the delivery of the agent to the site. Preferably, the deployment mechanism, when deployed, will maintain the vessel patent and allow substantial flow of blood to pass around it and perfuse the tissue distal to the treatment site for extended periods of time. Most desirably, the deployment mechanism will be a substantially rigid mechanical apparatus deployable and retractable by positive actuation from the proximal end of the apparatus. In addition, the apparatus should have a mechanism for delivering an agent to the treatment site which engages the treatment site along a porous contact surface and which is capable of injecting the agent at pressures sufficient to deeply penetrate tissue. The apparatus will preferably facilitate delivery of a variety of agent types and formulations, including pharmacological agents as well as endothelial cells for seeding purposes. Finally, the apparatus should be useful for treatment of blood vessels as well as a variety of other body organs.